These four illnesses, chronic fatigue syndrome (CFS/ME), multiple chemical sensitivity (MCS), fibromyalgia (FM) and post-traumatic stress disorder (PTSD) often occur together in the same individuals (they are comorbid) and share many symptoms in common (1,2). They also share a common pattern of case initiation: Each is often initiated (that is started) by a short-term stressor only to be followed by chronic illness that typically lasts for years and most often for life. These various similarities and overlaps among these four have led many scientists to suggest that they may share a common etiology (cause), however they have been uncertain what the cause may be. I will call these four illnesses multisystem illnesses, following the lead of some others, and will challenge here the claims they are unexplained and that even their symptoms are unexplained. What many have called the Gulf War Syndrome is a combination of all four (3; Chapter 10, ref.1).

It is my goal for this web page, to provide a detailed explanation for their overall mechanism and provide a proposed mechanism for the many symptoms and signs that they share. In web pages linked to this one, I will discuss some specific features of these illnesses and how each of these specific features may be generated by this same basic mechanism. I also provide more detailed support for the NO/ONOO- cycle mechanism outlined on this main web page, in these other web pages. My overall goal, here, is to outline the understanding of these illnesses that is documented in much greater detail in my book, “Explaining ‘Unexplained Illnesses’” (1), as well as in many other publications (2-12).

The stressors implicated in the initiation of these illnesses are summarized in Table 1.

The stressors indicated in bold are the ones most commonly implicated for that specific illness. It should be noted that the majority of such stressors are implicated in the initiation of more than one illness.

We have, here, 17 diverse stressors implicated in initiating these illnesses, leading one to ask, how they may do so? What I have argued, in my book (1) and elsewhere (2-10), is that each of these can act to increase nitric oxide levels. Each is reported to increase the levels of nitric oxide, or in three cases where that has not been studied, to stimulate a process which is itself known to increase nitric oxide. This is a striking common response and leads to the question about how nitric oxide increases might lead to chronic illness? My answer to that question is that nitric oxide, acting primarily through its oxidant product peroxynitrite, initiates a biochemical vicious cycle that is responsible, in turn, for the chronic illness. We have, then, an initial cause of illness (short-term stressor or stressors) acting to start this vicious cycle, with the cycle responsible for causing the chronic phase of illness. We are now calling the cycle the NO/ONOO- cycle after the structures of nitric oxide (NO) and peroxynitrite (ONOO-) but pronounced no, oh no! The cycle mechanism is outlined in Figure 1:

Fig. 1 legend. Vicious (NO/ONOO-) cycle diagram. Each arrow represents one or more mechanisms by which the variable at the foot of the arrow can stimulate the level of the variable at the head of the arrow. It can be seen that these arrows form a series of loops that can potentially continue to stimulate each other. An example of this would be that nitric oxide can increase peroxynitrite which can stimulate oxidative stress which can stimulate NF-kappaB which can increase the production of iNOS which can, in turn increase nitric oxide. This loop alone constitutes a potential vicious cycle and there are a number of other loops, diagrammed in the figure that can collectively make up a much larger vicious cycle. The challenge, according to this view, in these illnesses is to lower this whole pattern of elevations to get back into a normal range. You will note that the cycle not only includes the compounds nitric oxide, superoxide and peroxynitrite but a series of other elements, including the transcription factor NF-kappaB, oxidative stress, inflammatory cytokines (in box, upper right), the three different forms of the enzymes that make nitric oxide (the nitric oxide synthases iNOS, nNOS and eNOS), and two neurological receptors the vanilloid (TRPV1) receptor and the NMDA receptor.

The arrows in Fig. 1 represent 22 different mechanisms by which one element of the cycle can increase the levels of another element of the cycle. In my book (1) and elsewhere (2-4, 7-10), I discuss each of these 22. Of these 19 are well-documented and well-accepted biochemistry with three others less well documented. I recently reviewed the evidence for these last three and each of the three are now substantially better documented than when my book was written (10). Overall, there is massive evidence for the mechanisms proposed for the cycle, but what must be questioned is the physiological relevance of the cycle to these multisystem illnesses. Does the NO/ONOO- cycle really explain much of the etiologic (causal) mechanism of these illnesses?

There are five principles underlying the NO/ONOO- cycle as an explanatory model:

Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite and other cycle elements is produced and maintained. This principle predicts that the various elements of the NO/ONOO- cycle will be elevated in the chronic phase of illness.

.

Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.

Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells, the fundamental mechanisms are local. The consequences of this primarily local mechanism show up in the multisystem illnesses through the stunning variations one sees in symptoms and signs from one patient to another. Different tissue impact of the NO/ONOO- cycle mechanism is predicted to lead to exactly such variations in symptoms and signs. One also sees evidence for this fourth principle in published brain scan studies where one can directly visualize the variable tissue distribution in the brains of patients suffering from one of these illnesses.

Therapy should focus on down-regulating the NO/ONOO- cycle biochemistry. In other words, we should be treating the cause, not just the symptoms.

Of these principles, we have discussed 1 and 2 above. Principle 3 predicts that the symptoms and signs of illness can be generated by elevation of one or more elements of the cycle. Some examples of how symptoms and signs of illness may be explained by the cycle are discussed below.

Principle 4 is so important that it takes up an entire chapter in my book (1). Because nitric oxide, superoxide and peroxynitrite, the three chemical compounds most central to the NO/ONOO- cycle have relatively short half lives in biological tissues, they don’t diffuse very far from their site of origin in the body. Nitric oxide has the longest such half-life and it only diffuses about one millimeter from its origin or less. Furthermore, most of the mechanisms implicated by the arrows act at the cellular levels. The consequence of all of this is that the NO/ONOO- cycle may be elevated in one tissue of the body but an adjacent tissue may show little elevation and therefore have little impact by the cycle. This local nature of the cycle biochemistry means that we can have all kinds of variations in tissue impact from one patient to another, leading in turn to all kinds of variation in symptoms and signs from one individual to another. This striking variation in symptoms from one individual to another has been repeatedly been noted in these illnesses and has been one of the great puzzles about this group of illnesses. The variation can be easily explained by the local nature of the NO/ONOO- cycle mechanism.

The primarily local nature, outlined in Principle 4 does not imply that there are no systemic effects. The antioxidant depletion produced by local oxidative stress will be, to a substantial extent, systemic and some of the effects of the inflammatory cytokines are also systemic. These may, in turn, produce changes in neuroendocrine function and immune function that are also systemic. However the primary local nature helps us to understand the profound variations in symptoms and signs seen from one patient to another, how these different diseases may differ from one another and also differ from possible additional diseases that may share this NO/ONOO- cycle etiology, such as tinnitus (12).

Principle 5 states that the focus of therapy should be to down-regulate NO/ONOO- cycle biochemistry. In other words, therapy should focus on lowering the cause of illness, not just on treating symptoms. This is obviously an important principle for both patients suffering from these illnesses and for conscientious physicians or other medical care providers trying to treat them.

Two Additional NO/ONOO- Cycle Classes of Mechanisms

There are two important types of mechanisms that are important parts of the cycle but are NOT obvious from Fig. 1.

Firstly, there are several known mechanisms by which peroxynitrite, superoxide and nitric oxide can lower energy metabolism in mitochondria (the parts of the cells that generate energy in the form of ATP) (1,10). This lowering of energy metabolism is important both because it has a role in generating the symptoms of these diseases but also be because it is part of the cycle itself. Specifically, it has important roles in producing the increased NMDA activity and it probably also has an important role in producing elevated levels of intracellular calcium, a part of the cycle. There is substantial evidence for mitochondrial dysfunction in CFS/ME and fibromyalgia. And there is additional evidence from clinical trial studies that agents that improve mitochondrial function are helpful in the treatment of this group of illnesses.

A second important part of the cycle involves the depletion of a compound called tetrahydrobiopterin (often abbreviated BH4), a compound that it oxidized by peroxynitrite (1,11). BH4 is what is known as a cofactor in the nitric oxide synthases (NOSs), and tetrahydrobiopterin depletion produces what has been called partial uncoupling of the NOSs. When a NOS enzyme is missing BH4, it produces superoxide in place of nitric oxide. The consequence of this is that in cells and tissues that have high NOS activity and partial uncoupling, one has many adjacent enzyme molecules, some producing nitric oxide and others producing superoxide and these will react rapidly with each other to form more peroxynitrite. This will, in turn oxidize more BH4, producing more partial uncoupling. This reciprocal relationship between peroxynitrite and BH4 depletion is, then a potential vicious cycle within the larger NO/ONOO- cycle and may constitute the essential core of the cycle. Lowering of this central couplet will be expected to produce a clinical improvement in these diseases, but will produce an increase in nitric oxide. So while I think that the net effect of nitric oxide in these diseases is negative one, agents that increase nitric oxide by lowering this central couplet should be helpful.

A revised figure of the NO/ONOO- cycle is Diagrammed in Fig. 2 below, includes both of these additional types of mechanisms. In it peroxynitrite is abbreviated PRN and both BH4 depletion and ATP depletion are shown. Another thing is that in the upper left hand corner, the TRP receptors are shown. This is because it appears that two other members of the TRP family of receptors may have roles here, not just the vanilloid (TRPV1) receptor is shown in Fig. 1.

Figure 2

NO/ONOO- Cycle Mechanisms for the Generation of Shared Symptoms and Signs of Illness

It has been repeatedly claimed by many that these multisystem illnesses are unexplained and that even their symptoms and unexplained. Clearly for the NO/ONOO- cycle mechanism to be a plausible mechanism for these multisystem illnesses, it must be possible to explain the symptoms and signs of illness as being generated by one or more elements of the cycle. Such explanations are needed for both the specific symptoms and signs (discussed on the specific web pages) and the shared ones, discussed here. In Chapter 3 of my book, I discuss both the evidence for these shared symptoms and signs and how they may be generated by the NO/ONOO- cycle etiology. The mechanisms listed below are not presented as established mechanisms in these illnesses, but they are plausible mechanisms based on substantial scientific information. Each of these only occur in some multisystem illness sufferers, consistent with the striking variation of symptoms and signs that are a characteristic feature of these illnesses. Indeed it may be argued that the defining symptoms and signs of CFS/ME, MCS, FM and PTSD are found in all sufferers of each of these illnesses because we required them for the diagnosis.

Table 1-1 Explanations for Symptoms and Signs

Symptom/Sign

Explanation based on elevated nitric oxide/peroxynitrite theory

Energy Metabolism /Mitochondrial Dysfunction

Inactivation of several proteins in the mitochondrion by peroxynitrite; inhibition of some mitochondrial enzymes by nitric oxide and superoxide

Oxidative Stress

Peroxynitrite, superoxide and other oxidants

PET Scan Changes

Energy metabolism dysfunction leading to change transport of probe; changes in perfusion by nitric oxide, peroxynitrite and isoprostanes.

You can see, from the above, that there are plausible mechanisms for the NO/ONOO- cycle generating a number of shared symptoms and signs of these multisystem illnesses. I also discuss in my book (1) and on the web pages specific for one illness how the specific symptoms may be generated by the cycle. What one needs to do for each disease/illness to decide whether it is a good candidate for inclusion under the NO/ONOO- cycle, is to go through each of the five principles and determine how good the fit is for that specific disease/illness. And this is just what I have done for quite a number of diseases/illnesses in my book (1) and elsewhere (9,10,12).

I have also discussed three types of generic evidence that supports the existence of the NO/ONOO- cycle (1). By generic, I mean evidence not linked to any specific disease or illness. Those three are as follows:

1. Evidence from studies of two drugs that break down to release nitric oxide (nitroglycerine and nitroprusside) that each of them can cause mammalian tissues to synthesize increased amounts of nitric oxide via all three nitric oxide synthases. This supports the existence of a vicious cycle involving all three nitric oxide synthases, as predicted by the NO/ONOO- cycle, but does not say anything about other aspects of the cycle.

2. Evidence that increases in NMDA activity can increase essentially all of the NO/ONOO- cycle elements that were diagrammed in Figure 1. NMDA receptor activity directly increases intracellular calcium levels leading to increased nitric oxide levels. These studies show that most of the cycle elements can be increased simply by elevating intracellular calcium and nitric oxide, thus providing evidence for a cycle similar or identical to the NO/ONOO- cycle.

3. Hyperalgesia animal models involve all of the cycle elements shown in Figure 1 in the generation of excessive pain in hyperalgesia. It is difficult to explain this involvement unless the cycle ties all of these elements together.

The Tenth Paradigm of Human Disease

The basic proposal that is developed here and is amplified further in my book and in my other web pages, is that the NO/ONOO- cycle explanatory model is the tenth major paradigm of human disease. There are nine well-accepted paradigms listed below along with the NO/ONOO- cycle:

Major Disease Paradigms

1. Infectious diseases.

2. Genetic diseases.

3. Nutritional deficiency diseases.

4. Hormone dysfunction diseases.

5. Allergies.

6. Autoimmune diseases.

7. Somatic mutation/selection (cancer).

8. Ischemic cardiovascular diseases.

9. Amyloid (including prion) diseases.

10. NO/ONOO- cycle diseases

It can be seen from the above listing, that much of the progress of medical science over the past 140 years, has been focused on the development of a few disease paradigms as explanatory models. The high prevalence of MCS, FM, PTSD and CFS/ME and their high impact on the lives of sufferers, suggests that the NO/ONOO- cycle paradigm may be among the most important of these in terms of its explanation of current human disease.

There may be additional illnesses/diseases that may fit under this paradigm that may expand the importance of the tenth paradigm and I suggest 14 additional candidates for inclusion in Chapter 14 of my book (1) (discussed on my web page: Other Proposed NO/ONOO- Cycle Diseases). The criteria for possible inclusion are the five principles underlying the NO/ONOO- cycle explanatory model—the same principles that are being tested here for inclusion of the four multisystem illnesses.

The NO/ONOO- Cycle as an Explanatory Model of Multisystem Illnesses

One of the things that Kuhn in his famous book, “The Structure of Scientific Revolutions” makes clear is that new scientific paradigms are not only judged by the various types of data that may support them, they are also judged by how well they explain various types of previously unexplained properties. It is important, therefore, to consider how the NO/ONOO- cycle explains the many previously unexplained properties of the multisystem illnesses. I would like, therefore, to consider a few of these here:

1. How can such a variety of stressors act to initiate cases of these multisystem illnesses? They all act either by increasing nitric oxide levels in the body or by increasing other cycle elements. That is they all have the potential to initiate the NO/ONOO- cycle in certain regions of the body.

2. Why are these multisystem illnesses so variable from one patient to another? Because the NO/ONOO- cycle mechanism is basically local, being localized to different tissues in different individuals.

3. How do these different multisystem illnesses differ from one another? Each of them presumably must have NO/ONOO- cycle impact on one or more specific tissues in order to meet the diagnosis for that specific illness. I discuss on my other web pages, in my book (1) and elsewhere (4,6,9,10) which tissues may be involved.

4. How are the symptoms and signs of illness generated? Presumably through the impact of one or more cycle elements. We have discussed above some examples of how this may occur and how the specific symptoms may be generated is discussed on other web pages and elsewhere (1,4,6,7,9,10).

5. How should these illnesses be treated? By using agents that act to down-regulate different aspects of the NO/ONOO- cycle. These are discussed in more detail on my Therapy web page and also the Allergy Research Group Nutritional Support web page, as well as Chapter 15, ref. 1 and in (9,10).

6. Are these illnesses true diseases? Yes, albeit somewhat unusual ones. Because of the fundamentally local nature of the NO/ONOO- cycle, we have almost infinite possible variations of NO/ONOO- cycle caused diseases. That is we have a huge spectrum of disease and what we have done in defining these specific illnesses, is to more or less arbitrarily is to define a specific section of this spectrum as being, for example, fibromyalgia and another overlapping section as being CFS/ME. If one uses a different case definition for CFS/ME, it will define a somewhat different section of this huge spectrum. Medicine commonly views specific diseases as being qualitatively different from each other. For example, cases of tuberculosis are always caused by the tuberculosis bacillus whereas other infectious diseases are caused by different infectious agents. However, with NO/ONOO- cycle diseases, the whole concept of differential diagnosis on which so much of medicine is based, is called into question.